Association of Culprit Lesion Location With Outcomes of Culprit-Lesion-Only vs Immediate Multivessel Percutaneous Coronary Intervention in Cardiogenic Shock: A Post Hoc Analysis of a Randomized Clinical Trial | Acute Coronary Syndromes | JAMA Cardiology | JAMA Network
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Figure 1.  Study Flowchart
Study Flowchart

PCI indicates percutaneous coronary intervention; LM, left main coronary artery; pLAD, proximal left anterior descending artery.

Figure 2.  Kaplan-Meier Curves Comparing 1-Year Mortality
Kaplan-Meier Curves Comparing 1-Year Mortality

A, Kaplan-Meier curve comparing 1-year mortality in left main (LM) or proximal left anterior descending artery (pLAD) culprit lesion (CL) location vs other CL location. B, Kaplan-Meier curve comparing 1-year mortality in patients with left main or pLAD CL location vs other CL location treated by culprit-lesion-only percutaneous coronary artery intervention (CL-PCI) with optional staged revascularization vs immediate multivessel percutaneous coronary artery intervention (MV-PCI).

Table 1.  Baseline Clinical and Procedural Characteristics of Patients With Left Main or Proximal Left Anterior Descending Artery Culprit Lesion and Other Culprit Lesion Location According to Randomized Treatment Allocation
Baseline Clinical and Procedural Characteristics of Patients With Left Main or Proximal Left Anterior Descending Artery Culprit Lesion and Other Culprit Lesion Location According to Randomized Treatment Allocation
Table 2.  Clinical Outcomes at 30 Days and 1 Year After Randomization in Patients With Left Main or Proximal Left Anterior Descending Artery Culprit Lesion vs Other Culprit Lesion Location
Clinical Outcomes at 30 Days and 1 Year After Randomization in Patients With Left Main or Proximal Left Anterior Descending Artery Culprit Lesion vs Other Culprit Lesion Location
Table 3.  Clinical Outcomes at 30 Days and 1 Year After Randomization in Patients With Left Main or pLAD Culprit Lesion and Other Culprit Lesion Location According to Randomized Treatment Allocation
Clinical Outcomes at 30 Days and 1 Year After Randomization in Patients With Left Main or pLAD Culprit Lesion and Other Culprit Lesion Location According to Randomized Treatment Allocation
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Original Investigation
August 26, 2020

Association of Culprit Lesion Location With Outcomes of Culprit-Lesion-Only vs Immediate Multivessel Percutaneous Coronary Intervention in Cardiogenic Shock: A Post Hoc Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
  • 2Wilhelminenspital, Department of Cardiology, Vienna, Austria
  • 3ACTION Study Group, Centre Hospitalier Universitaire Pitié–Salpêtrière, Sorbonne Université Paris 6, Paris, France
  • 4Institut für Herzinfarktforschung, Ludwigshafen, Germany
  • 5Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute, Leipzig, Germany
  • 6Department of Internal Medicine/Cardiology/Angiology/Intensive Care Medicine, University Heart Center Luebeck, Luebeck, Germany
  • 7Department of Cardiology, Pneumology, and Intensive Care, University Hospital Regensburg, Regensburg, Germany
  • 8University Medical Centre Mannheim, First Department of Medicine, Faculty of Medicine, University of Heidelberg, Mannheim, Germany
  • 9Medical School, Sigmund Freud University, Vienna, Austria
JAMA Cardiol. 2020;5(12):1329-1337. doi:10.1001/jamacardio.2020.3377
Key Points

Question  Is there an association of culprit lesion location with outcomes of culprit-lesion-only percutaneous coronary intervention (PCI) vs immediate multivessel PCI in patients with multivessel disease, myocardial infarction, and cardiogenic shock?

Findings  In this post hoc analysis of a randomized clinical trial, culprit-lesion-only vs immediate multivessel PCI was associated with lower 1-year death if the culprit lesion was located in the left main or proximal left anterior descending artery but not if located in other coronary segments.

Meaning  Patients with multivessel disease, myocardial infarction, and cardiogenic shock may especially benefit from culprit-lesion-only PCI if the culprit lesion is located in the left main or proximal left anterior descending artery.

Abstract

Importance  Myocardial infarction with a culprit lesion located in the left main or proximal left anterior descending artery compared with other coronary segments is associated with more myocardium at risk and worse clinical outcomes.

Objective  To evaluate the association of culprit lesion location with outcomes of culprit-lesion-only percutaneous coronary intervention with optional staged revascularization vs immediate multivessel percutaneous coronary intervention in patients with multivessel disease, myocardial infarction, and cardiogenic shock.

Design, Setting, and Participants  Post hoc analysis of the Culprit Lesion Only Coronary Intervention vs Multivessel Coronary Intervention in Cardiogenic Shock (CULPRIT-SHOCK), an investigator-initiated randomized, open-label clinical trial. Patients with multivessel disease, acute myocardial infarction, and cardiogenic shock were enrolled at 83 European centers from April 2013 through April 2017.

Interventions  Patients were randomized to culprit-lesion-only percutaneous coronary intervention with optional staged revascularization or immediate multivessel percutaneous coronary intervention (1:1). For this analysis, patients were stratified by culprit lesion location in the left main or proximal left anterior descending artery group and other-culprit-lesion location group.

Main Outcomes and Measures  End points included a composite of death or kidney replacement therapy at 30 days and death at 1 year.

Results  The median age of the study population was 70 (interquartile range, 60-78 years) and 524 of the study participants were men (76.4%). Of the 685 patients, 33.4% constituted the left main or proximal left anterior descending artery group and 66.6% the other-culprit-lesion location group. The left main or proximal left anterior descending artery group had worse outcomes compared with the other-culprit-lesion location group (56.8% vs 47.5%; P = .02 for the composite end point at 30 days and 59.8% vs 50.1%; P = .02 for death at 1 year). In both groups, culprit-lesion-only vs immediate multivessel percutaneous coronary intervention was associated with a reduced risk of the composite end point at 30 days (49.1% vs 64.3% and 44.1% vs 50.9%; P for interaction = .27). At 1 year, culprit-lesion-only vs immediate multivessel percutaneous coronary intervention was associated with a significantly reduced risk of death in the left main or proximal left anterior descending artery but not the other-culprit-lesion location group (50.0% vs 69.6%; P = .003 and 49.8% vs 50.4%; P = .89; P for interaction = 0.02).

Conclusions and Relevance  In patients with multivessel disease with myocardial infarction and cardiogenic shock, a culprit lesion located in the left main or proximal left anterior descending artery vs other coronary segments was associated with worse outcomes. These patients may especially benefit from culprit-lesion-only percutaneous coronary intervention with optional staged revascularization, although further investigation is needed to confirm this finding.

Trial Registration  ClinicalTrials.gov Identifier: NCT01927549.

Introduction

Myocardial infarction (MI) complicated by cardiogenic shock (CS) is a life-threatening condition associated with high risk of early mortality.1,2 A culprit lesion (CL) located in the left main (LM) or proximal left anterior descending artery (pLAD), compared with other coronary segments, has been shown to be associated with higher risk for cardiac arrest, cardiogenic shock, and poor short-term and long-term survival.3,4 However, limited data exist on the association of the CL location with outcomes of patients presenting with multivessel coronary artery disease (MVD) and MI complicated by cardiogenic shock.5,6 In addition, it is uncertain whether there is an association of the CL location with outcomes of different revascularization strategies in these patients. The Culprit Lesion Only PCI vs Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial has found a significant benefit of culprit-lesion-only percutaneous coronary intervention with optional staged revascularization (CL-PCI) over immediate multivessel PCI (MV-PCI) with regards to risk of death or kidney replacement therapy at 30 days, which was consistent at 1-year follow-up.7,8

In this post hoc analysis of the CULPRIT-SHOCK trial, we aimed to determine short-term and long-term outcomes associated with LM/pLAD CL location vs other CL location and to evaluate the association of CL location with short-term and long-term clinical outcomes of the different revascularization strategies.

Methods
Study Population

The trial design and main results have been published elsewhere.7,8 In brief, CULPRIT-SHOCK was an investigator-initiated, multicenter, randomized, open-label clinical trial comparing CL-PCI with MV-PCI in patients with acute MI complicated by CS. Cardiogenic shock was defined as systemic blood pressure less than 90 mm Hg for at least 30 minutes or dependence on inotropes to maintain a systemic blood pressure of 90 mm Hg or greater, signs of pulmonary congestion, and signs of impaired organ perfusion with at least one of the following: altered mental status, cold, clammy skin, urine output less than 30 mL/h, or arterial lactate levels greater than 18.02 mg/dL (to convert to millimoles per liter, multiply by 0.111). Main trial inclusion criteria were planned early revascularization by means of PCI, MVD (defined as at least 2 major vessels [≥2 mm diameter] with >70% stenosis of the diameter), and an identifiable CL. The study was approved by the ethical committee in Leipzig, Germany, and by regional and national ethics review boards of all participating sites. Written informed consent was obtained with the use of a prespecified process that varied slightly according to country.8 Patients were randomized in a 1:1 fashion to undergo either CL-PCI or MV-PCI. The CL was treated first in all enrolled patients. Implantation of drug-eluting stents was recommended but not mandated. For patients randomized to CL-PCI, staged PCI was recommended on the basis of the patient’s clinical status and the presence of residual ischemia on objective testing.8 In patients from the MV-PCI group, all additional lesions (major coronary arteries with >70% stenosis of the diameter), including chronic total occlusions, were recommended to be treated with PCI immediately after treatment of the CL.

In this analysis, the study population was divided according to CL location in the LM/pLAD group and the other CL location (OCLL) group. With respect to the former, the CL was located either in the LM (ostial, shaft, or distal) or in the pLAD (pLAD was defined as the portion of LAD from the origin from LM up to the first septal perforator or first diagonal artery, whichever comes first). Regarding the latter, the CL was located in any other coronary segment. In each of these groups, the randomly assigned revascularization strategies (CL-PCI vs MV-PCI) were compared (Figure 1).

Clinical End Points

The primary end point of this analysis was a composite of death or kidney replacement therapy at 30 days. In addition, death, renal replacement, MI, rehospitalization for heart failure, staged or urgent repeated revascularization, stroke, and bleeding at 30 days and 1 year were evaluated. Furthermore, at 1 year, all-cause death and the composite end points of death or MI; death or rehospitalization for heart failure; and death, MI, or rehospitalization for heart failure were analyzed.

Statistical Analysis

All analyses were performed in the intention-to-treat population. Categorical variables are presented as percentages and were compared with the χ2 test. Continuous variables are presented as median with interquartile range (IQR) and compared with the Mann-Whitney-Wilcoxon test. Outcomes are presented as percentages and were compared by χ2 tests. Kaplan-Meier curves were used to show event rates over time according to group assignment (LM/pLAD vs OCLL and CL-PCI vs MV-PCI, respectively). Odds ratios (ORs) with 95% confidence intervals were generated using logistic regression analysis. Covariates to adjusted differences between CL location groups included history of hypertension, history of previous coronary artery bypass grafting, and TIMI III flow post PCI. Formal interaction testing was performed to evaluate possible interaction between revascularization strategy and CL location. All analyses were conducted with the use of SAS software, version 9.4 (SAS Institute). All tests were 2-sided, and P less than .05 was considered significant.

Results

Between April 2013 and April 2017, 1075 patients were screened for enrollment in the CULPRIT-SHOCK trial and 706 were randomized to either CL-PCI or MV-PCI. Informed consent and 1-year follow-up were available in 685 of these patients and constituted the study population. One patient was lost to follow-up within 30 days. Left main/pLAD CL was documented in 229 patients (33.4%), and OCLL was documented in 456 patients (66.6%) (Figure 1). Patients from the OCLL group had higher prevalence of hypertension and prior coronary artery bypass grafting as well as lower baseline left ventricular ejection fraction compared with the LM/pLAD group (eTable 1 in the Supplement). With regards to procedural characteristics, significantly lower TIMI flow before and after intervention was documented in the LM/pLAD vs the OCLL group. Mechanical circulatory support was significantly more often used in patients with LM/pLAD CL location compared with OCLL (eTable 1 in the Supplement). Baseline clinical and procedural characteristics of patients by randomized treatment allocation within the LM/pLAD group and OCLL group, respectively, are presented in Table 1.

Outcomes of Patients With LM/pLAD CL Location Compared With OCLL

At 30 days, the composite of death or kidney replacement therapy occurred significantly more often in patients with LM/pLAD CL location vs OCLL (56.8% [n = 130 of 229] vs 47.5% [n = 216 of 455]; P = .02). Similarly, the individual end points of death (54.6% [n = 125 of 229] vs 43.7% [n = 199 of 455]; 0.007) and MI (2.6% [n = 6 of 229] vs 0.2% [n = 1 of 455]; P = .003) were increased in the LM/pLAD vs the OCLL group. There were no differences between groups with regards to the individual end points of kidney replacement therapy, stroke, and bleeding at 30 days (Table 2). At 1 year, LM/pLAD CL location vs OCLL was associated with higher risk of death (59.8% [n = 137 of 229] vs 50.1% [n = 228 of 455]; P = .02) and MI (3.5% [n = 8 of 229] vs 1.1% [n = 5 of 455]; P = .03) (Table 2, and Figure 2A).

There were no differences between groups with regards to kidney replacement therapy, rehospitalization for heart failure, stroke, and bleeding (Table 2). The composite end points of death or MI (61.4% [n = 56 of 114] vs 51.2% [n = 74 of 115]; P = .01); death or rehospitalization for heart failure (62.0% [n = 140 of 229] vs 53.2% [n = 233 of 455]; P = .03); and death, MI, or rehospitalization for heart failure (63.3% [n = 145 of 229] vs 54.3% [n = 247 of 456]; P = .02) were significantly higher in the LM/pLAD group compared with the OCLL group at 1 year (Table 2).

After adjustment for differences in clinical and procedural characteristics between groups, the risk for death or kidney replacement therapy associated with LM/pLAD CL location vs OCLL was attenuated (OR, 1.37; 95% CI, 0.98-1.90; P = .07) but remained significant for death at 30 days and 1 year (OR, 1.45; 95% CI, 1.04-2.02 and OR, 1.46; 95% CI, 1.05-2.04, respectively) (eTable 2 in the Supplement).

Outcomes of Patients With LM/pLAD CL Location and OCLL by Revascularization Strategy

At 30 days CL-PCI vs MV-PCI was associated with a reduced risk of the composite of death and kidney replacement therapy in the LM/pLAD group (49.1% [n = 56 of 114] vs 64.3% [n = 74 of 115]; P = .02) and in the OCLL group (44.1% [n = 101 of 229] vs 50.9% [n = 115 of 226]; P = .16), with no significant interaction between CL location and revascularization strategy (P for interaction = .27). With respect to individual end points, CL-PCI vs MV-PCI was associated with a reduced risk of death only in the LM/pLAD group (45.6% [n = 52 of 114] vs 63.5% [n = 73 of 115]; P = .007 in the LM/pLAD group and 41.9% [n = 96 of 229] vs 45.6% [n = 115 of 226]; P = .43 in the OCLL group; P for interaction = .07) (Table 3). Staged or urgent repeated revascularization was increased in the CL-PCI vs the MV-PCI group regardless of CL location (Table 3).

At 1 year, CL-PCI vs MV-PCI resulted in a significantly lower risk of death in patients with LM/pLAD but not in patients with OCLL (50% [n = 57 of 114] vs 69.6% [n = 80 of 115]; P = .003 and 49.8% [n = 114 of 229] vs 50.4% [n = 114 of 226]; P = .89) with significant interaction between CL location and revascularization strategy (P for interaction = .02) (Table 3, Figure 2B). Similarly, the composite end points of death or MI, death or rehospitalization for heart failure and death, MI, or rehospitalization for heart failure were significantly lower in patients from the LM/pLAD group when treated with CL-PCI vs MV-PCI (Table 3). In both LM/pLAD and OCLL groups, staged or urgent repeated revascularization was performed more often in patients assigned to CL-PCI than in MV-PCI (28.9% vs 7%; P < .001 and 33.6% vs 10.6%; P < .001, respectively). Patients assigned to CL-PCI who underwent repeated revascularization had staged (vs urgent) revascularization in 61.7% (n = 21 of 34) and 54.5% (n = 42 of 77) in the LM-pLAD CL location group and the OCLL group, respectively. No significant differences were found in stroke and bleeding between CL-PCI and MV-PCI regardless of revascularization strategy (Table 3).

Discussion

The major findings of this analysis in patients presenting with MVD and acute MI complicated by CS are the following: (1) a CL located in the LM or pLAD vs other coronary segments is associated with worse short- and long-term outcomes, and (2) a strategy of CL-PCI with optional staged revascularization of non-CL as compared with immediate MV-PCI resulted in a reduced risk of death or kidney replacement therapy at 30 days regardless of CL location and in a 1-year mortality benefit in patients with LM/pLAD CL location. In consensus with these findings, previous studies documented worse outcomes associated with LM/pLAD CL location compared with OCLL.9-13 In hemodynamically stable patients, CL location in the LM or pLAD has been shown to be associated with higher risk of target lesion revascularization and MI.3 Moreover, in a real-world registry, infarctions in the LAD territory were associated with higher risk of death and heart failure compared with CL located in the left circumflex and right coronary artery.4 Data from the American College of Cardiology–National Cardiovascular Data Registry showed that in the setting of CS, CL location in the pLAD was an independent predictor of in-hospital mortality.5 These findings are not surprising because the LM and pLAD supply at least 50% of the left ventricular myocardium,12,14 and a CL located in these compared with other coronary segments results in more myocardium at risk.15 Nevertheless, a substudy of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial16 could not confirm an association of CL location and 1-year mortality, which was discussed to be attributed to advancements in interventional treatment of LM disease over the last decade. Furthermore, this analysis showed that a CL location in distal compared with proximal and mid coronary segments was associated with higher risk of mortality at 1 year.16 Authors hypothesized that the salvage of myocardium by PCI in patients with proximal and mid lesions was greater compared with patients with distal lesions. Because measurement of myocardial salvage by established methods, such as cardiac magnetic resonance imaging, had not been performed, these findings could not be fully explained. However, most importantly, more than 20% of the IABP-SHOCK II trial population had only single-vessel disease, which makes comparisons with our study results difficult.

Acute MI complicated by CS is associated with high morbidity and mortality.9,17 Early adequate treatment in an intensive cardiac care setting is crucial and should include invasive hemodynamic monitoring, supportive pharmacotherapy, and evaluation for the need of additional therapies including hypothermia and mechanical circulatory support.18 In addition, early revascularization has been shown to improve outcomes in these patients.17,19 With regards to patients presenting with MVD, the CULPRIT-SHOCK trial provided unique information and found lower risk of death or kidney replacement therapy for CL-PCI vs MV-PCI at 30 days and a persistent benefit at 1-year follow-up.7,8 According to the results of this analysis, patients with LM/pLAD CL location may especially benefit from a strategy focusing only on the CL with optional staged revascularization. In these patients, we found very high mortality at 1 year but a relative risk reduction of 47% (50.0% vs 69.6%) with CL-PCI vs MVI-PCI. As mentioned previously, the LM and pLAD supply a major part of the left ventricular myocardium. Revascularization of concomitant non-CL in other coronary segments during the primary PCI may not add more benefit but rather increase the risk of complications such as stent thrombosis, dissections, perforations, or slow flow.20 In addition, immediate MV-PCI increases the amount of contrast media use and thereby the risk of kidney failure.20,21 Furthermore, a prolonged coronary intervention may prolong the time out of the intensive care unit with suboptimal hemodynamic and respiratory management. Besides our data, only very limited information is available on this specific patient population. An analysis of the Korea Acute Myocardial Infarction Registry (KAMIR) registry22 on patients with MI and CS provided data on CL-PCI vs MV-PCI and analyzed the subgroup of patients with LM or LAD CL vs left circumflex or right coronary artery CL. In contrast to our results, the analysis of the KAMIR registry found favorable outcomes in patients treated with MV-PCI vs CL-PCI regardless of the CL location. These conflicting results may be explained by several differences of the patient populations and mainly by the study designs. The KAMIR study was an observational registry, and it cannot be excluded that selection bias has affected the results despite multivariate adjustment and sensitivity analyses. However, most importantly, the KAMIR registry included patients with staged revascularization in the MV-PCI group. In CULPRIT-SHOCK, patients with staged PCI were included in the CL-PCI group. In fact, staged PCI was encouraged in patients randomized to CL-PCI and represented 85.1% of patients who underwent repeated revascularization. Beneficial effects of complete revascularization performed as staged PCI were found by the COMPLETE trial23 and could also be an attractive strategy in patients presenting with CS, although special considerations apply. In patients with CS, longer periods until stabilization and recovery may have an effect on the timing of a staged approach.24

Interestingly, we found higher rates of rehospitalization for heart failure associated with CL-PCI vs MV-PCI within the OCLL group but not the LM/pLAD group; however, with no significant interaction between CL location and revascularization strategy. The underlying reasons for this finding are uncertain. It could be argued that these results might be attributed to the play of chance or a matter of competing risk. Patients from the CL-PCI survive more often and therefore have a higher likelihood to develop heart failure compared with those who underwent MV-PCI.7

Limitations

There are several limitations of this study that should be taken into account when interpreting the study results. First, this is a post hoc analysis of a randomized clinical trial. The analyses are possibly underpowered and results should be interpreted as hypothesis generating rather than conclusive. Second, there are various definitions of the pLAD, which makes comparisons between studies difficult. This analysis used the SYNTAX score definition of pLAD. Third, the CULPRIT-SHOCK trial enrolled patients with both STEMI and NSTEMI with CS. Results may differ between patients with STEMI and NSTEMI; however, analyses of these subgroups would have resulted in very small groups with no clinically meaningful results. Fourth, because there were no planned follow-up echocardiograms, we cannot rule out an effect of LVEF improvement on the lower risk of rehospitalization for heart failure in the OCLL group treated by MV-PCI as compared with CL-PCI.

Conclusions

In patients with multivessel disease presenting with acute MI and CS, a CL located in the LM and/or pLAD vs other coronary segments was associated with worse outcome. A strategy of CL-PCI with optional staged revascularization of non-CL compared with immediate MV-PCI resulted in a reduced risk of death or kidney replacement therapy at 30 days regardless of CL location. Patients with a CL located in the LM and/or pLAD may especially benefit from a CL-PCI strategy with regards to 1-year mortality, although further investigation is needed to confirm this finding.

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Article Information

Corresponding Author: Holger Thiele, MD, Department of Internal Medicine/Cardiology, Heart Center Leipzig at University of Leipzig, Struempellstr 39, 04289 Leipzig, Germany (holger.thiele@medizin.uni-leipzig.de).

Accepted for Publication: May 28, 2020.

Published Online: August 26, 2020. doi:10.1001/jamacardio.2020.3377

Author Contributions: Drs Thiele and Huber had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Thiele and Huber share senior authorship.

Concept and design: Farhan, Vogel, Zeymer, Desch, de Waha-Thiele, Thiele.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Farhan, Vogel, Thiele.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Farhan, Ouarrak, Schneider.

Obtained funding: Zeymer, Desch, de Waha-Thiele, Thiele.

Administrative, technical, or material support: Montalescot, Barthélémy, Zeymer, Desch, de Waha-Thiele, Sandri, Fuernau, Hauguel-Moreau, Thiele, Huber.

Supervision: Zeymer, Desch, Maier, Sandri, Akin, Thiele.

Conflict of Interest Disclosures: Dr de Waha-Thiele reports grants from German Heart Research Foundation, German Cardiac Society, European Union, Seventh Framework programme (FP7/2007-2013) grant agreement n602202 during the conduct of the study. Dr Schneider reports grants from European Union during the conduct of the study. Dr Zeymer reports grants and personal fees from AstraZeneca, BMS, Pfizer, Bayer, and Novartis and personal fees from Boehringer Ingelheim, MSD, Sanofi, Trommsdorf, and Amgen outside the submitted work. Dr Montalescot reports personal fees from Abbott, American College of Cardiology Foundation, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Menarini; grants from Actelion, Boehringer Ingelheim, Boston Scientific, Fédération Française de Cardiologie, ICAN, Idorsia, Lead-Up, Medtronic, MSD, Pfizer, Quantum Genomics, Sanofi, Servier; personal fees from Axis-Santé, Beth Israel Deaconess Medical, Brigham Women’s Hospital, China Heart House, Elsevier, Europa, Novo Nordisk, Occlutech, Partners, and WebMD outside the submitted work. No other disclosures were reported.

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